REPRODUCTIONANNIVERSARY REVIEW

Chronicling the discovery of interferon tau

Fuller W Bazer1 and William W Thatcher2 1Department of Animal Science, Texas A&M University, College Station, Texas, USA and 2Department of Animal Science, University of Florida, Gainesville, Florida, USA Correspondence should be addressed to F W Bazer; Email: [email protected]

Abstract

It has been 38 years since a protein, now known as interferon tau (IFNT), was discovered in ovine conceptus-conditioned culture medium. After 1979, purification and testing of native IFNT revealed its unique antiluteolyic activity to prevent the regression of corpora lutea on ovaries of nonpregnant ewes. Antiviral, antiproliferative and immunomodulatory properties of native and recombinant IFNT were demonstrated later. In addition, and IFNT were found to act cooperatively to silence expression of classical interferon stimulated genes in a cell-specific manner in ovine uterine luminal and superficial glandular epithelia. But, IFNT signaling through a STAT1/STAT2-independent pathway stimulates expression of genes, such as those for transport of glucose and amino acids, which are required for growth and development of the conceptus. Further, undefined mechanisms of action of IFNT are key to a servomechanism that allows ovine placental lactogen and placental growth hormone to affect the development of uterine glands and their expression of genes throughout gestation. IFNT also acts systemically to induce the expression of interferon stimulated genes that influence secretion of progesterone by the corpus luteum. Finally, IFNT has great potential as a therapeutic agent due to its low cytotoxicity, anti-inflammatory properties and effects to mitigate diabetes, obesity-associated syndromes and various autoimmune diseases. Reproduction (2017) 154 F11–F20

Embryonic death, uterine factors and pregnancy both of which limited litter size at term (Bazer et al. 1968, 1969). A number of historical events set the stage for research leading to the discovery of pregnancy recognition signals in pigs and species. Bazer and coworkers Concept of pregnancy recognition signaling (1969) noted that hormone-induced superovulation and While attention was being given to embryonic death, feeding high-energy feeds, to increase the number of uterine factors and pregnancy in pigs, Short (1979) ovulations in polytocous animals, led to greater rates clarified the terms luteotrophic, luteolytic, antiluteolytic of embryonic death due to inherent limitations within and pregnancy recognition signaling. Prostaglandin F individual embryos and to maternal limitations that 2α (PGF) was identified as the uterine-derived luteolytic restrict litter size or both. Embryonic death losses occur hormone responsible for regression of the CL and during the peri-implantation period of pregnancy (Boyd cessation of secretion of progesterone by luteal cells 1965) and increase following hormonal superovulation in nonpregnant subprimate (Schramm et al. (Fowler & Edwards 1957, Adams 1960, Hafez 1964) 1983). The antiluteolytic signals from pig and ruminant or the transfer of additional embryos to uterine horns conceptuses had not been identified in 1969, but it of mice (McLaren & Michie 1959, Adams 1960, Hafez was assumed that those signals inhibited luteolytic 1964). Bazer et al. (1969) postulated that a biochemical actions of PGF or abrogated the mechanism(s) for PGF- factor in the uterine lumen limited the number of induced luteolysis. Pregnancy recognition signals were blastocysts that undergo implantation and placentation. diverse (Flint et al. 1979). For example, available results This idea supported results of Krishnan and Daniel indicated the lack of need for pregnancy recognition (1967) who discovered blastokinin (also known as signals for dogs, ferrets and marsupials, but systemic uteroglobin). Blastokinin was reported to induce the effects of estrogens on functions of corpora lutea (CL) in development of morulae to blastocysts in rabbits. The pregnant pigs had been reported (Kraeling et al. 1975). fact that most embryonic deaths in pigs occur during Short (1979) reported that abnormal conceptuses failed the peri-implantation period of pregnancy (Gossett & to signal pregnancy recognition. Thus, the stage was set Sorensen 1959) suggested that the major causes were for research to identify pregnancy recognition signals failure of blastocysts to develop and/or uterine capacity, in mammals. This challenge was addressed in our

© 2017 Society for Reproduction and Fertility This paper is part of an Anniversary Issue celebrating 30 Years of Interferon-Tau. ISSN 1470–1626 (paper) 1741–7899 (online) The Guest Editor for this section was Professor R Michael Roberts. DOI: 10.1530/REP-17-0257 Downloaded from Bioscientifica.com at 09/27/2021 05:06:35PM Online version via www.reproduction-online.org via free access

10.1530/REP-17-0257 F12 F W Bazer and W W Thatcher laboratories at the University of Florida through research (Moor & Rowson 1966a,b, Rowson & Moor 1967, with pigs, sheep and cows. Moor 1968). They also found that a blastocyst must be transferred into the uterine horn ipsilateral to the ovary bearing a CL by Day 12 or Day 13 of the oestrous cycle Pregnancy recognition signaling in pigs for establishment of a successful pregnancy. This was Research on proteins in uterine secretions, their confirmed by a study in which they found that length endocrine regulation and their influence on embryonic of the oestrous cycle of ewes was only affected when survival in pigs (see Bazer 1975) led to research on conceptuses were flushed from the on or after mechanisms for establishment and maintenance of Day 13 of pregnancy (Moor & Rowson 1966a, Moor pregnancy in pigs, sheep and cows. Studies of the et al. 1969). Martal (1979) and Ellinwood and coworkers oestrous cycle and pregnancy in pigs revealed that (1979) reported an antiluteolytic factor in homogenates PGF was released into the uterine venous system in of sheep conceptuses collected on Days 14–15, but a pulsatile manner during the period of luteolysis in not Days 21–25 of pregnancy and homogenates of Day cyclic, but not pregnant gilts (see Bazer & Thatcher 14 and Day 15 conceptuses extended CL lifespan and 1977). Furthermore, it was discovered that the CL of pigs inter-oestrous intervals when infused into the uterine were not responsive to luteolytic effects of PGF until lumen of cyclic ewes (Rowson & Moor 1967, Ellinwood about Day 14 of the oestrous cycle; therefore, PGF was et al. 1979, Martal et al. 1979). The antiluteolytic factor ineffective as a hormone to synchronize estrus in pigs in the conceptus homogenates was confirmed to be (see Bazer et al. 1982). inactivated by heat and proteases. Martal et al. (1979) Our research on early pregnancy in pigs revealed named the antiluteolytic factor trophoblastin. Thus, it that blastocysts hatch from the zona pellucida between was established that maternal recognition of pregnancy Days 6 and 7, expand to large spherical blastocysts by signaling in ewes involved a protein secreted by the Day 10, and transition to tubular and filamentous forms conceptus between Days 12 and 21 after onset of estrus by Day 12 (1 mm diameter × 200 mm length) and Day and mating. 15 (800–1000 mm in length) of gestation (Geisert et al. 1982a,b,c). It was later established that elongating pig conceptuses secrete oestrogens (Perry et al. 1973, Discovery of interferon tau as the pregnancy Fischer et al. 1985), which are the pregnancy recognition recognition signal in signal in pigs (Bazer & Thatcher 1977). The endocrine- Our research on the estrogen-dependent endocrine- exocrine theory for pregnancy recognition in pigs was exocrine theory of pregnancy recognition in pigs (Bazer reported by Bazer and Thatcher (1977). The theory of & Thatcher 1977) biased our thinking toward the concept pregnancy recognition signaling in pigs was based on of oestrogen being the pregnancy recognition signal in results indicating that oestrogens, acting alone or in other livestock species, e.g., sheep and cows. Therefore, concert with prolactin, change the direction of secretion we studied steroid metabolism by uterine endometria of PGF from uterine epithelia from an endocrine to and conceptuses from sheep and cows. Results of those an exocrine direction. PGF is released from uterine studies provided no evidence for conceptus-derived epithelia into the vasculature of the uterus (endocrine oestrogens being the antiluteolytic factor secreted by secretion) in a pulsatile manner between Days 15 and conceptuses from sheep or cow conceptuses during 16 of the oestrous cycle to induce luteal regression. the period of pregnancy recognition signaling (see Eley However, PGF is secreted by uterine epithelia into the et al. 1979). Therefore, we cultured sheep conceptuses uterine lumen (exocrine direction) of pregnant pigs in medium containing radiolabeled amino acids where it is sequestered and metabolized (see Bazer & and analyzed culture medium to detect radiolabeled Thatcher 1977). This theory was confirmed and modified proteins that were synthesized de novo. We were using (see Zeicik et al. 2011). this method to identify proteins synthesized de novo and secreted into culture medium by explants of pig Pregnancy recognition signaling in ewes endometria (see Basha et al. 1980) (see Fig. 1). Ovine conceptus conditioned culture medium Rowson and Moor (1967) provided the first evidence that was first subjected to Sephadex G200 gel filtration ovine conceptuses secrete a substance(s) that extends CL chromatography, and we discovered a low-molecular- life-span in ewes and that the conceptus must be present weight radiolabeled protein that is now known as ovine in the uterine horn ipsilateral to the ovary bearing the interferon tau (IFNT) (Wilson et al. 1979). Later, bovine CL in order to prevent the regression of the CL. Those IFNT was identified using the same methods Lewis( et al. results indicated that the conceptus factor acted locally 1979). This research was supported by a United States to prevent CL regression. The ‘antiluteolytic factor’ was Department of Agriculture, Cooperative States Research thermolabile, degraded by proteases and produced by Service Grant No. 61615162 titled ‘Increasing Embryo ovine conceptuses between Days 12 and 21 of pregnancy Survival In Cattle’ awarded to Drs Thatcher and Bazer.

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Downloaded from Bioscientifica.com at 09/27/2021 05:06:35PM via free access Discovery of interferon tau F13

Figure 1 This figure illustrates the sequence of events that led to the discovery of interferon tau (IFNT) in ovine conceptus conditioned culture medium and identified in this figure of a two-dimensional polyacrylamide gel by green arrows. Details of how embryo transfer experiments contributed to discovery of pregnancy recognition signaling are provided in the text. Protein X, trophoblastin, ovine trophoblast protein 1 and type 1 trophoblast interferon were names given to the protein, which was finally named interferon tau.

The discovery of ovine IFNT was by Dr Bazer’s graduate with findings of Moor and Rowson (1966a) and Moor and student, Michael Wilson. After that, studies were led by Rowson (1966b). Intrauterine injections of semi-purified Dr Gregory Lewis, a postdoctoral fellow working with Drs oTP-1 between Days 12 and 14 of the oestrous cycle Thatcher and Bazer, and Dr James Godkin, a postdoctoral extended inter-estrous intervals and maintenance of CL fellow working with Drs R Michael Roberts and Bazer. that continued to produce progesterone (Godkin et al. Wilson switched majors to Agricultural Economics 1984). Those results strongly suggested that oTP-1 was and Dr Lewis focused his research on prostaglandins the antiluteolytic factor secreted by ovine conceptuses. secreted by the uterus and conceptus. Thus, much of the However, Vallet and coworkers (1988) provided clear early research on the protein originally called ‘Protein X’ evidence that highly purified oTP-1 alone, in the and later ovine trophoblast protein one (oTP1) was led total array of proteins secreted by ovine conceptuses, by Dr James Godkin. As noted previously, Martal et al. abrogated the luteolytic mechanism. (1979) purified the same protein as protein X/oTP1 and Immunocytochemical and in situ hybridization called it ‘trophoblastin.’ analyses revealed that oTP1 was expressed by In order to identify when during early pregnancy mononuclear trophectoderm cells (Godkin et al. 1984, the antiluteolytic protein(s) was secreted, sheep Farin et al. 1990, Guillomot et al. 1990) with maximal conceptuses from Days 10–25 of pregnancy were production between Days 14–16 of pregnancy. Day cultured in the presence of radioactive amino acids. This 15 ovine conceptuses released greater than 100 μg of allowed detection of de novo synthesized and secreted the protein in culture in a 24-h period (Ashworth & proteins in culture medium using two-dimensional Bazer 1989b), and expression of oTP-1 mRNA by the polyacrylamide gel electrophoresis and fluorography conceptus is greatest around Day 14 of pregnancy in (Godkin et al. 1982). One of the radiolabeled proteins in sheep and Day 20 of pregnancy in cattle (Hansen et al. culture medium had a molecular weight of 17–20 kDa, 1985, Stewart et al. 1987). However, low amounts of which was similar to the estimated size of the protein(s) IFNT are secreted by ovine conceptuses as early as originally identified using gel filtration chromatography. Days 8 and 10 of pregnancy (Ashworth & Bazer 1989a). Because the 17–20 kDa protein was the first major Expression of oTP1 mRNA is detectable on Days 10 and protein secreted by the ovine conceptus, it was initially 11, maximum after Day 13 and declines after Day 17 designated protein X, which was renamed ovine of pregnancy (Farin et al. 1990, Guillomot et al. 1990). trophoblast protein one (oTP-1) (Godkin et al. 1984). The decrease in IFNT gene expression occurred after oTP-1 was not synthesized and secreted by ovine attachment of conceptus trophectoderm to the uterine conceptuses beyond Day 21 of pregnancy, which agreed luminal epithelium during implantation. Thus, IFNT www.reproduction-online.org Reproduction (2017) 154 F11–F20

Downloaded from Bioscientifica.com at 09/27/2021 05:06:35PM via free access F14 F W Bazer and W W Thatcher is produced transiently by ovine conceptuses, with Mechanisms for the antiluteolytic effects of expression being greatest prior to the expression of interferon tau mRNAs for estradiol (ESR1) and oxytocin (OXTR) receptors in uterine epithelia between Days 13 and 14 Our research on mechanisms of action of IFNT as the of the oestrous cycle in ewes. antiluteolyic pregnancy recognition signal in ruminants Parallel studies with bovine and ovine oTP1 was conducted at the University of Florida and at Texas confirmed that they are antiluteolytic signals for A&M University. Dr John McCracken’s model of the pregnancy in both species (Knickerbocker et al. 1986, ‘progesterone block’ for regulation of the oestrous cycle Helmer et al. 1987, 1989, Thatcher et al. 1989, Meyer in ewes (see Schramm et al. 1983) provided the basis for et al. 1995, Tysseling et al. 1997). Using ovine IFNT, our hypotheses on mechanisms whereby IFNT signals Newton and coworkers (1996) demonstrated that it pregnancy recognition in sheep and other ruminant is antiluteolytic when injected into the uterine lumen species. We tested the hypothesis that progesterone (P4) of goats. blocks the expression of receptors for estradiol (ESR1) and oxytocin (OXTR) for a finite period of time, 10–12 days, after which time progesterone (P4) downregulates Cloning the gene for oTP1 the expression of its own receptor (PGR) to allow upregulation of expression of ESR1 and OXTR genes. Dr James Lauderdale, a colleague of Drs Thatcher and Then, pulsatile release of oxytocin from the posterior Bazer, obtained permission for Dr Russell Anthony, pituitary gland and CL elicit secretion of luteolytic a postdoctoral fellow working with Drs Roberts and pulses of PGF from uterine epithelia on Days 15 and Bazer, to work in the laboratories of Drs K R Marotti 16 to cause regression of the CL and return to oestrus and H G Polites at the Upjohn Company to clone the by the ewe. The following evidence indicates that IFNT gene for oTP1. However, with Dr Roberts move from alone is the pregnancy recognition component in ewes the University of Florida to the University of Missouri, and other ruminant species: (1) IFNT directly silences cloning of the oTP1 gene was continued by Dr Kaz transcription of the ESR1 gene and, indirectly, the Imakawa, a graduate student in Dr Roberts’ laboratory. E2-induced expression of OXTR in uterine luminal and Imakawa and coworkers (1987) and Stewart and superficial glandular epithelia to abrogate development coworkers (1987) cloned the gene for oTP-1, and it was of the endometrial luteolytic mechanism involving found to be a member of the Type I interferon alpha oxytocin-induced luteolytic pulses of PGF (Spencer et al. (IFNA) family of proteins. The identity between the 1995a,b, 1998, Fleming et al. 2001, 2006); (2) basal 172 ovine oTP-1 and the 165 amino acid concentrations of PGF and PGE2 in maternal blood are bovine IFNA1 mRNA and protein was found to be 63% greater in pregnant than cyclic ewes due to continued and 50%, respectively (Roberts 1991, 1993). However, expression of prostaglandin endoperoxide synthase 2 homology between oTP1 and bovine IFN omega 1 (PTGS2) (Charpigny et al. 1997b, Simmons et al. 2010); (IFNW1) mRNAs and proteins was 85% and 72%, (3) IFNT silences the expression of ESR1, which prevents respectively. Thus, oTP1 is in a distinct subgroup of the oestradiol (E2) from upregulating the expression of PGR Type I IFN family (Imakawa et al. 1987). Because of in endometrial epithelia (Fincher et al. 1986, Vallet et al. its unique developmental expression by trophectoderm 1988, Mirando et al. 1990, Spencer et al. 1995b) and and its relatedness to other Type I IFNs (alpha, beta, (4) downregulation of expression of PGR in uterine omega), oTP1 was given the name interferon tau epithelia is required for expression of P4-induced and (IFNT) by the International Interferon Society (see IFNT-stimulated genes that support the development of Roberts 1991). the conceptus (Spencer et al. 1998, Choi et al. 2001, Bazer et al. 2014). Production of recombinant ovine interferon tau Caprine IFNT, secreted between Days 16 and 21 of gestation, is the pregnancy recognition signal that and its biological activities prevents pulsatile release of luteolytic PGF by uterine Using a highly purified native IFNT, we demonstrate epithelia and extends CL lifespan in goats (Newton its potent antiviral (Pontzer et al. 1988, 1990), et al. 1996). Bovine IFNT, secreted between Days 12 antiproliferative (Pontzer et al. 1991) and and 38 of pregnancy, prevents the secretion of luteolytic immunosuppressive (Pontzer et al. 1994, Newton et al. pulses of PGF by uterine epithelia and blocks effects 1996) properties, as well as insight into the structural of exogenous E2 and oxytocin to stimulate pulsatile motif of IFNT (Jarpe et al. 1994). Subsequently, we release of PGF by bovine uterine epithelia. Expression produced and expressed a synthetic gene for ovine IFNT of ESR1 and OXTR mRNAs are either downregulated or using the Pichia pastoris yeast system. The recombinant ESR1 and OXTR are less abundant or less responsive to IFNT has immunosuppressive, antiviral, antiproliferative E2 and oxytocin in endometria of pregnant compared to and antiluteolytic properties equivalent to native IFNT cyclic cows or cows receiving intrauterine injections of (Ott et al. 1991, Van Heeke et al. 1996). either ovine or bovine IFNT (Knickerbocker et al. 1986,

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Downloaded from Bioscientifica.com at 09/27/2021 05:06:35PM via free access Discovery of interferon tau F15

Helmer et al. 1987, 1989, Thatcher et al. 1989, Meyer progestamedins (e.g., fibroblast growth factors 7 and 10, et al. 1995, Tysseling et al. 1997). and hepatocyte ) from uterine stromal cells Interferon tau, the sole factor produced by the and IFNT act on uterine epithelia or other uterine cell conceptus that prevents development of the endometrial types via novel non-classical cell signaling pathways, luteolytic mechanism in sheep (Vallet et al. 1988), does independent of PGR and STAT1. Progestamedins and not stabilize expression of PGR in uterine epithelia IFNT can signal via mitogen-activated protein kinases during pregnancy (Spencer & Bazer 1995, 1996, Spencer (MAPK) and phosphoinositide-3 kinase (PI3K) to affect et al. 1995b). Rather, IFNT acts on uterine luminal and gene expression and uterine receptivity to implantation superficial glandular epithelia to inhibit transcription (Platanias 2005). All Type I IFNs bind the same receptor, of ESR1 and OXTR genes and abrogate development but may activate novel cell-specific signaling pathways. of the endometrial luteolytic mechanism (Spencer Thus, IFNT may differentially affect gene expression & Bazer 1996, Spencer et al. 1998, Fleming et al. in uterine luminal and superficial glandular epithelia 2001). The increases in expression of ESR1 and OXTR vs uterine glandular epithelium and stromal cells. This mRNAs in uterine luminal and superficial glandular cell-specific gene expression in the ovine uterus is epithelia between Days 11–17 post-oestrus in cyclic due to expression of IRF2 only by uterine luminal and sheep do not occur in pregnant ewes (Spencer & Bazer superficial glandular epithelial cells, which is likely 1995) or in cyclic ewes in which recombinant ovine responsible for the silencing expression of classical IFNT is injected into the uterine lumen (Spencer et al. interferon stimulated genes by uterine luminal and 1995c). Thus, oxytocin is unable to induce secretion superficial glandular epithelia (Spencer et al. 1998, of luteolytic pulses of PGF. However, basal production Choi et al. 2001). of PGF is greater in pregnant than cyclic ewes as IFNT In addition to signaling pregnancy recognition in does not inhibit the expression of PTGS2 in uterine LE/ ruminants, IFNT limits expression of classical interferon- sGE (Charpigny et al. 1997b, Simmons et al. 2010). stimulated genes to ovine uterine glandular epithelium The molecular mechanisms involved in IFNT silencing and stromal cells, which do not express IRF2. However, of expression of ESR1 is likely due to IFNT-inducing there are many P4-induced and IFNT-stimulated genes expression of IFN regulatory factor two (IRF2), a potent expressed by uterine luminal and superficial glandular repressor of transcription, in uterine luminal and epithelia that lack both PGR and STAT1 (signal superficial glandular epithelia (Spencer et al. 1998, transduction and activator of transcription 1). This is Choi et al. 2001, Fleming et al. 2001). In the absence because IFNT induces expression of IRF2 in uterine of ESR1, ovine uterine epithelia do not express OXTR luminal and superficial glandular epithelia in ewes to (Fleming et al. 2006). The promoter region of the OXTR silence expression of ISGs, but induces expression of gene does not contain an estrogen response element, many novel genes that support growth and development rather ESR1 binds to SP1 elements and interacts with of the conceptus. Those genes include: wingless-type two GC-rich SP1-binding sites, located within 140 bp of MMTV integration site family member 7A (WNT7A), the translational start site for OXTR (Fleming et al. 2006). LGALS15 (galectin 15), HIF2A (hypoxia-inducible factor Mutation analyses of the OXTR promoter revealed that 2A), CTSL (cathepsin L), CST3 (cystatin C), SLC5A1 the proximal SP1 sites mediated ESR1 action as well as (solute carrier family 5, sodium/glucose cotransporter, basal activity of the promoter (Fleming et al. 2006). member 1), GRP (gastrin releasing peptide), HSD11B1 In contrast to the ovine OXTR gene, the bovine OXTR (11 beta hydroxysteroid dehydrogenase type 1), IGFBP1 gene lacks a classical palindromic oestrogen response (insulin-like growth factor binding protein 1) and SLC7A2 element (Bathgate et al. 1998), and there is no change in (solute carrier family 7, cationic amino acid transporter, ESR1 expression in uterine epithelia between pregnant y+ system, member 2) (Bazer et al. 2009, 2015a,b). and nonpregnant cows (Robinson et al. 1999). Thus, Inhibition of the classical (JAK):STAT cell pregnancy and IFNT may alter expression of OXTR mRNA signaling pathway by IRF2 likely allows expression of independent of ESR1 in the endometrium of cattle. IRF2 the P4-induced and IFNT-stimulated genes to increase can regulate the expression of the bovine OXTR gene in response to both the progestamedins and IFNT via (Telgmann et al. 2003) suggesting its common role as an MAPK and PI3K cell signaling in uterine luminal and effector of the antiluteolytic actions of IFNT in bovine superficial glandular epithelia. These include genes endometria for the establishment of pregnancy. for transport of glucose (SLC2A1 and SLC5A11) and amino acids (SLC7A1 and SLC7A2) into the uterine lumen to stimulate proliferation of trophectoderm Progesterone-induced and interferon tau-stimulated cells by activating the glutamine:fructose-6-phosphate amidotransferase (GFAT)-mediated FK506-binding genes in the ovine uterus protein 12-rapamycin-associated protein 1 (FRAP1, In ewes, progesterone (P4) induces and IFNT further formerly mTOR) signaling pathway. Arginine also stimulates the expression of many genes. However, a affects fetal–placental growth and development through fundamental unanswered question is whether actions of effects on synthesis of nitric oxide (NO) and polyamines www.reproduction-online.org Reproduction (2017) 154 F11–F20

Downloaded from Bioscientifica.com at 09/27/2021 05:06:35PM via free access F16 F W Bazer and W W Thatcher that stimulate vascular functions, as well as DNA and Interferon tau induced effects distal to the protein synthesis for proliferation and differentiation conceptus/uterine complex of cells, respectively. However, expression of major In addition to the paracrine effects of IFNT secreted by histocompatibility complex class I molecules and β2- microglobulin genes that regulate immune rejection the trophectoderm on the underlying endometrium, responses is silenced in ovine uterine luminal and IFNT-stimulated genes (ISGs) are expressed in blood superficial glandular epithelia to protect the conceptus cells and cellular components of the CL. IFNT secreted allograft from rejection by the maternal immune system. (Oliveira et al. 2008) or infused into the uterine vein (Bott et al. 2010) of sheep initiated a peripheral antiviral response (e.g., increased expression of interferon Interferon tau and the servomechanism for stimulated gene 15 (ISG15) in immune cells in maternal blood) to possibly protect the pregnancy from maternal maintenance of pregnancy viral infection. The endocrine action of IFNT impacts Interferon tau is a component of the servomechanism the CL to induce luteal resistance to PGF (Antoniazzi for the maintenance of pregnancy in ewes. The et al. 2013), enhances expression of ISG15 in luteal servomechanism provides for reciprocal communication cells (Oliveira et al. 2008, Yang et al. 2010) and/or alters between the conceptus and endometrium during functions of immune cells within the CL to maintain CL implantation and synepitheliochorial placentation in function and pregnancy (Shirasuna et al. 2015). ewes (Spencer et al. 1999, 2007, Stewart et al. 2000, A bovine animal model was developed to further 2001, Noel et al. 2003). This concept is based on understand the integration of signalling between IFNΤ evidence that IFNT extends lifespan of CL initially and and immune cells that contribute to maintenance that placental lactogen (CSH1) and/or placental growth of progesterone secretion by large luteal cells in hormone (GH1) secreted by the trophectoderm/chorion pregnancy (Shirasuna et al. 2015). Compared to non- from Day 15 to term, and Days 35–65 of pregnancy, pregnant cows, the CL of pregnant cows on Day 16 respectively, reinforce the antiluteolytic effects of IFNT. after insemination have greater expression of mRNAs However, there were no independent or interactive for ISG15 and 8 (IL8), as well as IL8 protein, effects of CSH1 and GH1 on luteal maintenance and while expression of TNFα mRNA is reduced in pregnant function in ewes. Importantly, both CSH1 and GH1 compared to non-pregnant cows. Furthermore, CL of affected the development and function of uterine glands, pregnant cows have greater numbers of . but only if the uterus was first exposed to intra-uterine Although IFNΤ does not directly affect the secretion IFNT between Days 11 and 21 and then intra-uterine of progesterone (P4) by large luteal cells or migration CSH1, GH1 or CSH1 and GH1 between Days 16 and of neutrophils, IFNΤ increased expression of ISG15 29 after onset of estrus. During gestation, endometrial and IL8 mRNAs in large luteal cells. Both IL8 and gland hyperplasia occurs between Days 15 and 50 ISG15 stimulate migration in vitro, but IFNΤ of pregnancy and hypertrophy of the uterine glands was ineffective. If neutrophils were pre-treated with to increase surface area for maximal production of IFNΤ, then IL8 induced a greater neutrophil migration histotroph occurs after Day 60 of gestation. Sequential response. When large luteal cells were co-cultured with exposure of the ovine endometrium to E2, P4, IFNT, CSH1 neutrophils, secretion of P4 increased in response to and GH1 constitutes a ‘servomechanism’ responsible IFNΤ compared to amounts of P4 secreted when large for activating and maintaining endometrial remodeling, luteal cells were cultured alone or co-cultured with secretory function and uterine growth during gestation. neutrophils, but not treated with IFNT. IL8-stimulated Downregulation of PGR in uterine epithelial cells is secretion of P4 by large luteal cells cultured alone. The a prerequisite for P4-induced expression of genes in increase in neutrophils and IL8 within the CL of pregnant uterine GE that include SPP1 (secreted phosphoprotein cows suggests additional complementary involvement 1), UPTI (uterine plasmin trypsin inhibitor) and STC1/ of IFNΤ within the CL to maintain secretion of P4 and STC2 (stanniocalcin). Treatment of ewes with a pregnancy in cows. This model indicates that IFNΤ combination of P4 and E2 increases the expression of stimulates expression of IL8 in luteal cells that activates ESR1 and PGR in uterine GE, and the increase in ESR1 and induces migration of neutrophils, which stimulate inhibits expression of SPP1 and UPT1. Thus, IFNT is large luteal cells to increase or sustain secretion of P4 a prerequisite to the developmentally programmed in cows during early pregnancy. Thus, IFNT appears to sequence of events, mediated by specific paracrine- induce both antiluteolytic and complementary intra- acting factors at the conceptus-endometrial interface, ovarian effects that ensure maintenance of a functional responsible for both remodeling of the inter-caruncular CL for maintenance of pregnancy. Further investigations endometrium and differentiated functions of uterine GE into the integration of the immune and endocrine to increase production of histotroph for fetal-placental systems of early pregnancy, via IFNΤ acting distal to the growth during gestation. conceptus/endometrial unit are warranted to advance

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Downloaded from Bioscientifica.com at 09/27/2021 05:06:35PM via free access Discovery of interferon tau F17 understanding of mechanisms for maintaining the CL of of the antioxidant tetrahydrobiopterin. Collectively, early pregnancy. metabolic profiles were improved Tekwe( et al. 2013). Because IFNT stimulates oxidation of energy substrates and reduces obesity in ZDF rats, IFNT has important Potential therapeutic effects of oral interferon tau implications for treating obesity-related diseases. The effects of IFNT are not limited to ruminant species Using a diet-induced obesity mouse model treated and pregnancy. There are reports that IFNT induces orally with IFNT in water (8 µg/kg/day), insulin sensitivity immunological tolerance in several animal models. in obese mice was enhanced. This was due to a significant Matings between DBA/2 × C57B mice result in high decrease in secretion of proinflammatory and rates of fetal resorptions, but treatment of dams with increases in anti-inflammatory (M2) and exogenous IFNT prevents this pregnancy wastage in an T-reg cells in white adipose tissue (Ying et al. 2014, 2016). IL10-dependent manner (Chaouat et al. 1995, 2004). In Thus, IFNT can significantly mitigate obesity-associated the experimental allergic encephalomyelitis (EAE) mouse systemic insulin resistance and tissue inflammation by model, IFNT suppresses EAE by stimulating IL10, i.e., a Th2 controlling polarization and the population response (Soos et al.2002). Treatment of NOD mice with of anti-inflammatory T-reg cells. IFNT either orally, intraperitoneally or subcutaneously delays or inhibits development of diabetes (Sobel et al. Summary 2008). During pregnancy and in response to IFNT, MHC class I and β2 microglobulin gene expression is silenced The discovery of IFNT as the pregnancy recognition in uterine epithelia, but stimulated by IFNT in uterine signal in ruminants and understanding of its mechanism stroma and glandular epithelium as a component of of action have been established over the past few the mechanism(s) to prevent immune rejection of the decades. This knowledge had led to translational conceptus allograft (Choi et al. 2003). These results research to explore its use for pregnancy diagnosis in indicate that IFNT affects the relative abundance of ruminants by measuring it directly in maternal blood Th1 and Th2 cytokines produced by immune cells to or assessing increases in the expression of interferon- favour a Th2 anti-inflammatory phenotype of tolerance stimulated genes by immune cells in maternal blood. expected to abrogate the progression of inflammatory Further, the anti-inflammatory roles of IFNT in treatment diseases in humans and animals. IFNT inhibits human of autoimmune diseases such as obesity, diabetes, immunodeficiency virus (HIV) replicationin vitro more multiple sclerosis, psoriasis and others remain to be effectively than human IFNA, particularly in human explored through clinical trials to evaluate the potential macrophages wherein it decreased intracellular HIV therapeutic roles of the novel IFNT in treatment of RNA and inhibited reverse transcription of viral RNA into human and animal conditions. proviral DNA (see Maneglier et al. 2008). Interferon tau increased synthesis of cellular antiviral factors including 2′,5′ oligoadenylate synthetase 1, ribonuclease L and Declaration of interest myxovirus resistance 1, mouse, homolog of proteins, as The authors declare that there is no conflict of interest that could well as the anti-inflammatory cytokines be perceived as prejudicing the impartiality of this review.. and .

Funding Interferon tau and obesity This work was supported by funding from the United States Recognizing the link between inflammation, obesity and Department of Agriculture (12-14-100-9962, 1972-1974; 616- the anti-inflammatory properties of IFNT, studies were 15-162, 1976-1980; 91-37203-6548, 1991-1992; 9202755, initiated to determine the effects of oral IFNT on time of 1992-1994; 91-37203-6548, 1995-1998; 98-01983, 1998- onset of Type 2 diabetes (T2D), oxidation of glucose and 2000; 2009-01722, 2009-2012; the National Institutes of fatty acids in insulin-sensitive tissues, energy expenditure, Health (HD10436, 1980-1983; HD10436, 1983-1990; body mass and tissue weights in Zucker diabetic fatty HD26006, 1989-1994; HD32534, 1996-2008; and the U.S.A.- (ZDF) rats, an animal model of T2D and obesity (see Israel Binational Agricultural Research and Development Fund Tekwe et al. 2013). Oral administration of IFNT (8 µg/ (OEP 9604563, 1996-1999). kg body weight/day) reduced oxidative stress, increased oxidation of energy substrates to CO2 in insulin-sensitive tissues, decreased white adipose tissue by 40%, increased Acknowledgements brown adipose tissue by 46%, increased whole-body The authors gratefully acknowledge the contributions of energy expenditure and ameliorated oxidative stress in graduate students, postdoctoral fellows and faculty member at insulin-sensitive tissues (i.e., decreased ratios of oxidized both the University of Florida and Texas A&M University who to reduced glutathione), and increased concentrations contributed to the research on pregnancy recognition signaling www.reproduction-online.org Reproduction (2017) 154 F11–F20

Downloaded from Bioscientifica.com at 09/27/2021 05:06:35PM via free access F18 F W Bazer and W W Thatcher in pigs and ruminants. They have not cited each paper relevant Charpigny G, Reinaud P, Tamby JP, Créminon C, Martal J, Maclouf to the history of IFNT, but additional papers can be obtained by J & Guillomot M 1997 Expression of cyclooxygenase-1 and -2 in ovine endometrium during the estrous cycle and early pregnancy. querying PubMed. Between 1970 and 1985, the order in which Endocrinology 138 2163–2171. (doi:10.1210/endo.138.5.5148) authors were listed was the order of contribution to the work. Chaouat G, Meliani AA, Martal J, Raghupathy R, Elliot J, Mosmann T & After 1985, the corresponding author is the last author listed. Wegmann TC 1995 IL-10 prevents naturally occuring fetal loss in the Trainees were first author on most papers published based on CBA X DBA/2 mating combination, and local defect in IL-10 production results of their research for their respective graduate degree. in this abortion-prone combination is corrected by in vivo injection of IFN-τ. Journal of Immunology 154 4261–4268. Chaouat G, Ledée-Bataillea N, Dubancheta S, Zourbasa S, Sandra O & Martal J 2004 Th1/Th2 paradigm in pregnancy:paradigm lost? International Archives of Allergy and Immunology 134 93–119. References (doi:10.1159/000074300) Choi Y, Johnson GA, Burghardt RC, Berghman LR, Joyce MM, Taylor KM, Adams CE 1960 Prenatal mortality in the rabbit, Oryctolagus cunicululs. Stewart MD, Bazer FW & Spencer TE 2001 Interferon regulatory factor Journal of Reproduction and Fertility 1 36–44. 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endo.136.11.7588227) F2α, E and 13,14-dihydro-15-keto-prostaglandin F2α in cyclic ewes. Spencer TE, Becker WC, George P, Mirando MA, Ogle TF & Bazer FW Journal of Reproduction and Fertility 84 493–504. (doi:10.1530/ 1995b Ovine Interferon-τ regulates expression of endometrial receptors jrf.0.0840493) for estrogen and oxytocin, but not progesterone. Biology of Reproduction VanHeeke G, Ott TL, Strauss A, Ammaturo D & Bazer FW 1996 High 53 732–745. (doi:10.1095/biolreprod53.3.732) yield expression and secretion of the pregnancy recognition hormone Spencer TE, Ing NH, Ott TL, Mayes JS, Becker WS, Watson GH, Mirando ovine interferon-τ by Pichia pastoris. Journal of Interferon Research 16 MA & Bazer FW 1995c Intrauterine injection of ovine interferon-τ 119–126. (doi:10.1089/jir.1996.16.119) (IFN-τ) alters oestrogen and oxytocin receptor expression in the Wilson ME, Lewis GS & Bazer FW 1979 Proteins of ovine blastocyst origin. endometrium of cyclic ewes. Journal of Molecular Endocrinology 15 Proceedings of the Society for the Study of Reproduction 101A. 203–220. (doi:10.1677/jme.0.0150203) Yang L, Wang XL, Wan PC, Zhang LY, Wu Y, Tang DW & Zeng SM 2010 Spencer TE, Ott TL & Bazer FW 1998 Expression of interferon regulatory Up-regulation of expression of interferon-stimulated gene 15 in the factors one and two in the ovine endometrium: effects of pregnancy bovine corpus luteum during early pregnancy. Journal of Dairy Science and ovine interferon tau. Biology of Reproduction 58 1154–1162. 93 1000–1011. (doi:10.3168/jds.2009-2529) (doi:10.1095/biolreprod58.5.1154) Ying W, Kanameni S, Chang CA, Nair V, Safe S, Bazer FW & Zhou B 2014 Spencer TE, Ott TL, Gertler A, Gootwine E & Bazer FW 1999 Effects Interferon tau alleviates obesity-induced adipose tissue inflammation of recombinant ovine interferon tau, placental lactogen and growth and insulin resistance by regulating macrophage polarization. PLoS ONE hormone on the ovine uterus. Biology of Reproduction 61 1409–1418. 9 e98835. (doi:10.1371/journal.pone.0098835) (doi:10.1095/biolreprod61.6.1409) Ying W, Tseng A, Chang CA, Wang H, Lin YL, Kanameni S, Brehm T, Spencer TE, Johnson GA, Bazer FW & Burghardt RC 2007 Fetal-maternal Morin A, Jones B, Criscitiello M et al. 2016 miR-150 regulates insulin interactions during the establishment of pregnancy in ruminants. sensitivity through controlling B cell functions. Scientific Reports 6 Reproduction 64 379–396 (doi:10.5661/rdr-vi-379) 20176. (doi:10.1038/srep20176) Stewart HJ, McCann SH, Barker PJ, Lee KE, Lamming GE & Flint AP Ziecik AJ, Waclawik A, Kaczmarek MM, Blitek A, Jalali BM & 1987 Interferon sequence homology and receptor binding activity of Andronowska A 2011 Mechanisms for the establishment of pregnancy ovine trophoblast antiluteolytic protein. Journal of Endocrinology 115 in the pig. Reproduction in Domestic Animals 46 (Supplement 3) 31–41. R13–R15. (doi:10.1677/joe.0.115R013) (doi:10.1111/j.1439-0531.2011.01843.x) Stewart DM, Johnson GA, Gray CA, Schuler LA, Burghardt RC, Joyce MM, Bazer FW & Spencer TE 2000 Prolactin receptor and uterine milk protein expression in the ovine uterus during the estrous cycle and early pregnancy. Biology of Reproduction 62 1779–1789. (doi:10.1095/ biolreprod62.6.1779) Stewart D, Johnson GA, Vyhlidal CA, Burghardt RC, Safe SH, Yu-Lee L- Y, Bazer FW & Spencer TE 2001a Interferon tau activates multiple STAT proteins and has complex effects on interferon-responsive gene Received 1 May 2017 transcription in ovine endometrial epithelial cells. Endocrinology 142 First decision 12 June 2017 1786–1794. (doi:10.1210/endo.142.5.8138) Stewart DM, Johnson GA, Vyhlidal CA, Burghardt RC, Safe SH, Yu-Lee Revised manuscript received 4 July 2017 LY, Bazer FW & Spencer TE 2001b Interferon-tau activates multiple Accepted 26 July 2017

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